Deborah Marcellus

Donor leukocyte infusions for multiple myeloma

Donor leukocyte infusion (dli) has well-documented activity in cml, but the role of dli in other diseases is less well defined. to evaluate the strategy in multiple myeloma (mm) we evaluated 25 mm patients from 15 centers who were treated with dli. patients with persistent or recurrent disease after allogeneic bmt received dli from the original marrow donor (23 matched related, one mismatched family, and one matched unrelated). chemotherapy was given before dli in three patients. two of 22 patients responded completely to dli alone and three patients responded to the combination of dli and chemotherapy. nine patients who had not had sufficient disease control after dli were given additional dlis; five of these patients had either complete (two) or partial (three) responses. thirteen of 25 evaluable patients developed acute gvhd and 11 of 21 evaluable patients developed chronic gvhd; all responders developed gvhd. no patients developed post-dli pancytopenia. four patients had responses which lasted >1 year after DLI, three patients had responses which lasted <1 year, and three patients had ongoing responses but with follow-up <1 year. In conclusion, DLI has anti-myeloma activity but the strategy is limited by no response or short duration of response in a significant percentage of patients and by significant GVHD in the majority of the responders. Bone Marrow Transplantation (2000) 26, 1179–1184.

Immunotherapy with rituximab during peripheral blood stem cell transplantation for non-Hodgkin's lymphoma

Peripheral blood stem cell grafts from patients with lymphoma are often contaminated with neoplastic cells. Administration of a lymphoma-specific monoclonal antibody before collecting stem cells may be one way of reducing the contamination. Similarly, an antibody after transplantation at a time of minimal residual disease may increase the efficacy of the procedure. The objective of this study was to determine the safety of using rituximab as both an in vivo purging agent and a posttransplantation adjuvant. Eligible patients with lymphoma received 375 mg/m2 rituximab intravenously IV) on day 1, 2.5 g/m2 cyclophosphamide IV on day 4, and 10 microg/kg per day filgrastim starting on day 5 and continuing until completion of leukapheresis. Patients subsequently received a standard preparative regimen and then received 375 mg/m2 rituximab IV 7 days after platelet independence was achieved. Twenty-five patients (14 men, 11 women; median age, 51 years) were enrolled. Of the 25 patients, 23 received transplants after at least 2.0 x 10(6) CD34+ cells/kg were harvested. As determined with a sensitive polymerase chain reaction assay, 6 of 7 stem cell products tested were free of tumor contamination. All patients engrafted promptly, and the rituximab infusions were well tolerated. Transient neutropenia of uncertain etiology occurred in 6 patients a median of 99.5 days post-transplantation. An additional patient developed progressive pancytopenia. Rituximab used as an in vivo purging agent and adjuvant immunotherapy with peripheral blood stem cell transplantation for non-Hodgkins lymphoma is a well-tolerated regimen. However, the ultimate determination of efficacy will require the results of ongoing studies.

Psychological Distress Among Adult Patients Being Evaluated for Bone Marrow Transplantation

A sample of 437 patients being evaluated for bone marrow transplantation (BMT) completed interviews and questionnaires to assess their psychosocial adjustment. Nearly a third of the patients (31%) showed some degree of depression on the Center for Epidemiologic Studies Depression Scale. Scores on the Profile of Mood States Scale also indicated that these BMT candidates were experiencing a high level of psychological distress. This distress was found to be predicted by low scores on the Self-Rated Karnofsky Performance Scale and on scales measuring mastery and dispositional optimism. The value of assessing the levels of psychological distress and psychosocial resources of patients being evaluated for BMT and for providing necessary psychiatric interventions are discussed.

Impact of age on outcome of patients with cancer undergoing autologous bone marrow transplant.

PURPOSE We examined the impact of age on outcomes in patients with cancer undergoing autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS All 506 adult patients who underwent ABMT at the Johns Hopkins Oncology Center between January 1987 and January 1994 were studied. A total of 405 patients were aged 18 to 49 years and 101 were aged > or = 50. The effect of age and other prognostic variables on transplant-related mortality (TRM), relapse, and event-free survival rates were analyzed. RESULTS Patients aged > or = 50 years has a 2.24-fold increased risk of TRM. Although relapse rates were not different based on age, the increased TRM rate resulted in a slight decrease in overall event-free survival in the older patients. Causes of death were not different by age and were mainly related to preparative regimen toxicity. Length of hospital stay and hospitalization costs were not increased in the older patients. CONCLUSION While the TRM rate was higher in older patients, relapse rates were not increased. Nearly 25% of older patients were expected to be cured of the disease. These data support the use of ABMT in eligible older patients, at least up to the age of 65.

Long-term follow-up of T cell-depleted allogeneic bone marrow transplantation in refractory multiple myeloma: importance of allogeneic T cells

Multiple myeloma may be cured by myeloablative conditioning and allogeneic blood or marrow transplantation (alloBMT), but this occurs at the expense of high transplant-related mortality. In an endeavor to reduce procedure-related toxicity, this study retrospectively evaluated the safety, tolerability, and efficacy of T cell depletion by counterflow centrifugal elutriation before alloBMT. Fifty-one patients with stage II (6) or III (45) multiple myeloma received alloBMTs using T cell depletion by elutriation. Fifty-three percent (27 of 51) of patients had primary refractory disease at the time of transplantation, 10% (5 of 51) had relapsed disease, and 4% (2 of 51) had refractory relapsed disease. The median age was 49 (range, 32 to 62) years, and the median time from diagnosis to transplantation was 9 (range, 4 to 58) months. Patients had received a median of 1 (range, 1 to 3) regimen and 4 (range, 2 to 16) cycles of chemotherapy. In this population, transplant-related mortality rate was 24% (12 of 51) with 2 patients dying of graft-versus-host disease (GVHD). Thirty-one of 39 evaluable patients have experienced relapse, and the probability of progression-free survival 5 years after alloBMT alone is 16%. Sixteen patients were given donor lymphocyte infusions (DLI) at the time of relapse (n = 11) or for persistent disease 1 year after transplantation (n = 5). Acute or chronic GVHD was seen in 63% (10 of 16) of patients given DLI. Responses were seen in 8 of 16 patients (6 complete response [CR], 2 partial response [PR]) with 6 of 8 responding patients having GVHD. Five recipients of DLI remain in a continuous CR, ranging from 3 to 64 months in duration. Thus, like chronic myelogenous leukemia, allogeneic T cells appear to have potent antimyeloma activity that is critical for achieving a cure. DLI-induced remissions of multiple myeloma can be durable, even in patients with refractory multiple myeloma. Unlike chronic myelogenous leukemia, the antimyeloma effect of allogeneic T cells rarely occurs in the absence of clinically significant GVHD.

Cancer Problems in Living and Quality of Life After Bone Marrow Transplantation

This study was conducted to develop an objective problems-in-living scale to identify the needs of cancer survivors after a demanding treatment such as bone marrow transplantation (BMT). A total of 99 adult BMT survivors completed questionnaires containing the 29 items included in the Cancer Problems-In-Living Scale (CPILS). These BMT survivors were most concerned about return of their illness or relapsing, the future, fatigue, not physically being able to have sexual intercourse, changes in their physical appearance, being concerned about infection and crowds, difficulty in obtaining adequate insurance, losing health insurance by changing jobs, and difficulty in meeting medical expenses. The CPILS showed a good level of internal consistency (α = .91). The hypothesis that BMT survivors who had lower levels of physical functioning would experience more problems with living was supported by correlation (.48, p < .001) of the CPILS with the Self-Rated Karnofsky Performance Scale. The construct validity of the CPILS was further supported by a significant negative correlation (−.66, p < .002) with the scores of BMT survivors on a quality-of-life measure, the Satisfaction with Life Domains Scale for BMT.

Immune modulation in autologous bone marrow transplantation: cyclosporine and gamma-interferon trial

From March 1994 to November 1994, 16 patients with high risk hematological malignancies were entered in a phase I clinical trial, designed to confirm the toxicity of cyclosporine and gamma interferon given to induce autologous graft-versus-host disease (GVHD) after autologous bone marrow transplantation (ABMT). This trial was based on the results in a rodent model, in which cyclosporine given after ABMT induces an autoimmune syndrome (autologous GVHD) identical to allogeneic GVHD. Further, this autologous GVHD is associated with a graft-versus-tumor effect augmented by interferon that upregulates MHC class II expression on normal and tumor cells, the target of the cytolytic T cells in autologous GVHD. In this trial, cyclosporine 1 mg/kg/day was given from the day of bone marrow reinfusion until the completion of the interferon and gamma-interferon. Gamma-interferon at 0.025 mg/m2 every other day was started when the total white cell count was >200 cells/ml for 2 consecutive days and continued for a total of 10 doses after ABMT. The preparative regimens were busulfan and cyclophosphamide, or cyclophosphamide with total body irradiation. All patients received 4HC-purged marrow grafts. Median age was 45 years (range 19–68). The diagnoses included chemo-resistant non-Hodgkin’s lymphoma (10), acute lymphoblastic leukemia (two), chemo-resistant Hodgkin’s disease (two), acute myeloid leukemia (one), and multiple myeloma (one). Median absolute neutrophil count recovery was 25.5 days (range 19–46 days). Median platelet count recovery was 40.5 days (range 28–279 days). There were nine deaths, two were related to transplant toxicity (infection), while the other seven were due to relapse. Event-free survival with a median of 964 days (range 19–1441 days of follow-up was 44%. In conclusion, treatment with cyclosporine, and gamma-interferon after ABMT was well tolerated and did not impair engraftment. Further studies with a larger number of patients are required to document any beneficial anti-tumor effect of autologous GVHD induction after ABMT.

Quality of life and social support of patients being evaluated for bone marrow transplantation

A sample of 437 patients completed self-report measures of quality of life and social support while they were being evaluated for bone marrow transplantation (BMT) at The Johns Hopkins Oncology Center. Generally, the candidates showed reasonably high levels of quality of life (QOL) on the Satisfaction with Life Domains Scale (SLDS), their present ranking on the Cantril Self-Anchoring Ladder of Life, and their scores on the Bradburn Positive Affect Scale. The level of QOL of these candidates for transplant was significantly related to their level of social support. Both availability and adequacy of social support for these transplant candidates were found to be significantly related to QOL as measured by the SLDS. Availability of social support as measured by patient membership in religious and other organizations was significantly related to Positive Affect but not Negative Affect. The Family APGAR and Relational Support Scales measures of social support were significantly correlated with both Positive and Negative Affect.

CD34+ stem cell augmentation of elutriated allogeneic bone marrow grafts : results of a phase II clinical trial of engraftment and graft-versus-host disease prophylaxis in high-risk hematologic malignancies

Although T cell depletion of allografts used in BMT has reduced GVHD, it has been associated with inferior engraftment and an increased risk of relapse. We have found that T cell depletion by counterflow centrifugal elutriation (CCE) also results in depletion of CD34+ stem cells. In order to determine if the discarded CD34+ cells would improve engraftment, we undertook a phase II trial of allogeneic BMT in which 110 patients (median age 43) with a variety of hematologic malignancies received CD34+ stem cell augmented, elutriated marrow grafts. The T cell-depleted grafts were tightly controlled and contained a mean of 4.3 × 107 mononuclear cells/kg, 3.3 × 106 CD34+ cells/kg, 1.5 × 105 CFU-GM/kg and 5.5 × 105 CD3+ T cells/kg. Median time to engraftment of granulocytes (>500/μl) was 16 days and of platelets (>50 000/μl) was 25 days, comparable to that seen with unmanipulated marrow. No mixed hematopoietic chimerism was observed that was not associated with disease relapse. The four patients (3.6%) who failed to engraft were all at high risk because of prior donor transfusions or underlying marrow disorders. The incidence of GVHD was dependent on the duration of cyclosporin A (CsA) immunosuppression. In patients who received CsA for ⩾80 days, the incidence of clinically significant acute GVHD (>stage 1) and extensive, chronic GVHD was 5% and 11%, respectively. Peri-transplant (⩽100 day post-BMT) mortality for this group of patients was 15%. Event-free survival in selected subsets of patients compared favorably to previous studies in which patients received unmanipulated marrow allografts.

Phase I study of escalating doses of low-dose-rate, locoregional irradiation preceding Cytoxan-TBI for patients with chemotherapy-resistant non-Hodgkin’s or Hodgkin’s lymphoma

PURPOSE In patients in whom bone marrow transplantation (BMT) fails, recurrence often occurs at sites known to have contained disease before initiating BMT. The purpose of this study was to find the maximal tolerable dose of locoregional irradiation (LRT) between 1000 and 2000 cGy that could be integrated with our Cytoxan-total body irradiation (TBI) BMT conditioning regimen in the treatment of lymphoma. METHODS AND MATERIALS Patients had Hodgkins or non-Hodgkins lymphoma in chemotherapy-refractory relapse. All patients received LRT to a maximum of three sets of fields encompassing either all current or all previously known sites of disease. Cytoxan-TBI consisted of cyclophosphamide 50 mg/kg daily for 4 days followed by TBI of 1200 cGy given in four fractions. RESULTS Twenty-one patients were enrolled. Radiation Therapy Oncology Group Grade 3 in-field acute toxicity was observed in 1 patient at each dose level up to 1500 cGy and in 3 of 6 patients receiving 2000 cGy. Clinically evident late toxicities were limited to hypothyroidism and one second malignancy occurring outside the LRT fields. CONCLUSION Low-dose-rate, LRT with concurrent Cytoxan-TBI before BMT has acceptable rates of in-field toxicity for doses up to 1500 cGy in five fractions. This regimen safely permits the use of a total combined radiation dose of up to 2700 cGy during 2 weeks, with encouraging in-field response rates in treatment-refractory patients.